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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.

Grid stability becomes an issue when incorporating renewable distribution generation into an electrical grid due to voltage fluctuations. This work presents an innovative solution which assists grid planners in carrying out technical and economic analysis of future grids and in taking decisions based on it. A set of tools allows the determination of the renewable energy sources and energy storage systems impact to a given grid concerning technical and economic indicators. Using these tools, a study was conducted comparing model predictive control with photovoltaics-curtailment, volt-watt and volt-var methods for the control of photovoltaics and energy storage power in an existing grid. Some highlights of the analysis are: (i) the given grid supports maximal photovoltaics penetration level of 120% without exceeding the ±10% voltage level limits; (ii) the model predictive control method aiming at the minimization of power exchange in a grid with 60% storage penetration allowed significant increase of photovoltaics penetration to 190% and reduced the maximum voltage level to 1.089pu; (iii) a user-centered design and development of the interface for grid planners resulted in a system usability scale score of 63.9. The tools enable the grid planner to take decisions when planning the future grid.

Additional file 1: Supplementary material. A combined document including all supplementary tables (Tables S1-S11), figures (Figs. S1-S7), and code (Text S1).

In continuous concrete T-beams, tension flange plays a remarkable role for the hogging moment capacity at the support area. When precast beams are connected as a continuous structure, longitudinal reinforcement is spread in the flange overhangs at the negative moment area of the continuity connection, which causes longitudinal shear in the tension flange's web-flange junction. The level of reinforcement spreading influences the magnitude of in-plane forces at the junction, which can cause the flanges to crack and eventually separate from the web. This separation must be prevented by providing transversal reinforcement in the flanges. Longitudinal shear between web and flange and the required transversal reinforcement are experimentally and computationally studied in cantilever composite T-beams with the flange in tension. A comparison of the experimental and computational results revealed that longitudinal shear distribution in accordance with conventional beam theory does not always yield safe side results. Analyses made with a particularly drawn truss model and the modified compression field theory are in better agreement with the experimental results. publishedVersion

Gene fusions can act as oncogenic drivers and offer targets for cancer therapy. Since fusions are rare in colorectal cancer (CRC), their universal screening seems impractical. Our aim was to investigate gene fusions in 62 CRC cases with deficient MLH1 (dMLH1) and BRAFV600E wild-type (wt) status from a consecutive real-life series of 2079 CRCs. First, gene fusions were analysed using a novel FusionPlex Lung v2 RNA–based next-generation sequencing (NGS) panel, and these results were compared to a novel Idylla GeneFusion assay and pan-TRK immunohistochemistry (IHC). NGS detected seven (7/62, 11%) NTRK1 fusions (TPM3::NTRK1, PLEKHA6::NTRK1 and LMNA::NTRK1, each in two cases, and IRF2BP2::NTRK1 in one case). In addition, two ALK, four RET and seven BRAF fusions were identified. Idylla detected seven NTRK1 expression imbalances, in line with the NGS results (overall agreement 100%). Furthermore, Idylla detected the two NGS–identified ALK rearrangements as one specific ALK fusion and one ALK expression imbalance, whilst only two of the four RET fusions were discovered. However, Idylla detected several expression imbalances of ALK (n = 7) and RET (n = 1) that were found to be fusion negative with the NGS. Pan-TRK IHC showed clearly detectable, fusion partner-dependent staining patterns in the seven NTRK1 fusion cases. Overall agreement for pan-TRK antibody clone EPR17341 was 98% and for A7H6R 100% when compared to the NGS. Of the 62 CRCs, 43 were MLH1 promoter hypermethylated (MLH1ph) and 39 were RASwt. All fusion cases were both MLH1ph and RASwt. Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS.

Dyslipidemia is a major risk factor for cardiovascular disease. While common genetic variants are known to modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesteremia and other genetic disorders of lipid metabolism. Aiming to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits, we analyzed whole-exome and whole-genome sequencing data of 481 and 573 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 97 serum lipid, apolipoprotein, or other metabolic phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance (NMR) technology. Single variant analysis identified a novel association between LIPC p.Thr405Met (rs113298164) and serum apolipoprotein-A1 levels (p=7.8×10−8). In the APOB gene, we identified novel associations at two protein-truncating variants (PTVs) resulting in lower serum apolipoprotein B levels (p=5.6×10−4). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, and GTF3C5 (p−6). The RBM47 gene is required for apolipoprotein-B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III levels was led by a rare 21 base pair Ala496-Ala502 deletion; as replication, the burden of rare deleterious variants in RBM47 was associated with TG-to-HDLC ratio in WES of 20,917 individuals (p=0.0093). Two PAVs in GTF3C5 were highly Finnish-enriched and associated with cardiovascular phenotypes in external data, whereby the TRMT5 p.Ser185Cys lead variant was associated with stroke phenotypes. Altogether, we identified both novel variant associations in known lipid genes, as well as novel genes implicated in lipoprotein metabolism.

Universal testing of microsatellite instability (MSI) is recommended for colorectal cancer (CRC) and endometrial cancer (EC) to screen for Lynch syndrome and to aid in assessing prognosis and optimal treatment. We compared the performance of Idylla MSI test to immunohistochemistry (IHC) of mismatch repair (MMR) proteins in consecutive series of 100 CRC and 108 EC samples, as well as in retrospective series of 28 CRC and 33 EC specimens with known deficient MMR protein expression. The concordance between the Idylla test and IHC was 100% in all CRC samples (n=128) but lower in EC samples (87.2%; n=141). In the EC samples, sensitivity of Idylla test was 72.7% and specificity 100%. EC MSI/dMMR agreement was 85.4% for MLH1, 87.5% for MSH2, and only 35.3% for MSH6. When we analyzed 14 EC samples that were discrepant, i.e., dMMR using IHC and microsatellite stable using Idylla, with microsatellite markers BAT25 and BAT26, we found four cases to be replication error (RER) positive. All RER positive cases were deficient for MSH6 protein expression. We also re-analyzed EC samples with variable tumor cellularity to determine the limit of detection of the Idylla test and found that a 30% or higher tumor cellularity is required. We conclude that Idylla MSI test offers a sensitive and specific method for CRC diagnostics but is less sensitive in EC samples especially in the case of MSH6 deficiency. Supplementary Information The online version contains supplementary material available at 10.1007/s00428-021-03082-w.

Understanding oncogenic epigenetic mechanisms in brain tumors is crucial for improved diagnosis and treatment. Recently DNA methylation has proven to be powerful for brain tumor characterization and diagnostic classification. To evaluate tumor type specific features, we compared atypical teratoid/rhabdoid tumors (AT/RTs), medulloblastomas (MBs), and choroid plexus tumors with each other by integrating DNA methylation (507 samples), gene expression (120 samples), and transcription factor (TF) -binding data. Different tumor entities were used to find unique changes affecting each of the entities and further to identify functions driven by these changes. Our results provide insight on how the aberrant DNA methylation induces oncogenesis of AT/RTs. These tumors are known for their aggressiveness and exceptionally low mutation rates. Our results suggest that in AT/RT, elevated DNA methylation masks the binding sites of TFs such as NEUROD1, ASCL1 and MYCN driving neural development. DNA methylation in AT/RTs is also associated with reduced gene expression for specific neural regulators such as NEUROG1 and NEUROD2. For MBs, DNA methylation patterns predict a more advanced differentiation state. In MB, we found masked TF binding sites for TFs such as REST and ZEB1 that normally inhibit neural differentiation. We then wanted to further characterize DNA methylation and compared these tumors to pluripotent stem cells (PSCs) and normal fetal brain samples. As a result, we were able to find two different regulatory programs in AT/RTs: One in which DNA methylation is similar to PSCs and which harbors mostly neural TF binding sites. Second program has AT/RT-specific DNA methylation, and these sites are uniquely associated with polycomb repressive complex 2 members. However, this second program also covers neural TF binding sites and is likely to have relevance in oncogenic regulation.

The oncogenic protein Bcr-Abl has two major isoforms, p190Bcr-Abl and p210Bcr-Abl. While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210Bcr-Abl, p190Bcr-Abl exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190Bcr-Abl CML patients, p190Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.

Context Parathyroid carcinoma (PC) is extremely rare. Prognosis is poor, with no known evidence-based systemic therapies. We previously reported complete remission in a patient with metastasized parathyroid carcinoma and high tumor MGMT promoter methylation status who was treated with temozolomide. Objective To study MGMT promoter methylation status in an additional set of aggressive parathyroid tumors. Design/Setting The study included 12 patients: 7 with sporadic and 5 with familial primary hyperparathyroidism (two of the latter carried a CDC73 gross deletion). Patient 9 is the previously described patient with PC and high MGMT methylation status. Her daughter (patient 12) had surgery for severe primary hyperparathyroidism due to atypical parathyroid adenoma during pregnancy. Eleven patients thus had PC and one had atypical parathyroid adenoma. MGMT promoter methylation status was determined from DNA extracted from primary (n = 10) or metastatic (n = 2) tumors. A mean methylation level >20% was considered high. Patient 11 had metastatic PC and received temozolomide cycles. Results Only the previously published patient (patient 9) had high tumor MGMT promoter methylation status. This was not a characteristic of the atypical parathyroid adenoma of the daughter (patient 12). Patient 11 (CDC73 intragenic deletion) has disseminated PC, low MGMT promoter methylation, and stable disease on follow-up after temozolomide treatment. Conclusion High MGMT promoter methylation status seems rare in PC. However, as demonstrated in other neuroendocrine tumors, some patients with disseminated PC might benefit from temozolomide. Demonstration of high methylation status could be a predictor of positive response to temozolomide treatment.

There is a Blood Commentary on this article in this issue.

The objective of the current study is to investigate and evaluate the flexural behavior of the continuity connection of precast prestressed concrete beams in negative bending when the tendons are located at the compression side. The experimental program included four T-shaped composite cantilever beams which were loaded up to failure. The main variable of the tests was the amount of prestress force of the connected precast beams. The reinforcement ratio of continuity connection was high. The ultimate flexural capacities and moment-curvature relations were calculated theoretically. A comparison was then carried out between both the experimental and theoretical results. These experiments revealed that prestress force did not influence the ultimate hogging moment capacity of the continuity connection, but it had an effect on its soffit's compression cracking and spalling of the concrete cover before failure. This study also indicated that confinement of the concrete had a massive influence on the connection's behavior, and it increased both its negative moment capacity and ductility. publishedVersion

Blended education embraces various combinations of face-to-face and online teaching. It has become a normal part of higher education degree programmes. Since the late 1990s, the Open University of the University of Jyväskylä (JYUOpen) has been offering online and blended education for its rapidly growing number of students. For many years now, Finnish education has ranked high in PISA research. Furthermore, the University of Jyväskylä has been successful in global rankings, especially in the field of education (Shanghai Ranking: 36, QS World University Rankings: 51–100 and Times Higher Education: 67). In order to present the success factors of the Finnish education system, we offered our first MOOC in the autumn semester of 2016 and the blended model of it in the autumn semester of 2017. By utilising our MOOCs and offering face-to-face teaching on campus, we can enhance deeper understanding of different education topics and organise collaboration opportunities for our exchange and degree students. In the autumn semester of 2020, we offered this blended course fully online by utilising synchronous online meetings. In this article, we presentstudent feedback and teacher experiences of our blended model. Based on the preliminary analysis, student feedback on the blended model is constructive and positive. Student feedback has been an essential part of the development of the MOOC courses. nonPeerReviewed

Common variable immunodeficiency and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is however implicated. To study whether somatic mutations in CD4+ and CD8+ T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta sequencing was used to characterize CD4+ and CD8+ T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in common variable immunodeficiency and 48% in controls. Clonal hematopoiesis-associated variants in both CD4+ and CD8+ cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immune- and proliferative functions, such as STAT5B (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4+ and CD8+ cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.

Introduction One third of patients with myelodysplastic syndrome (MDS) will relapse after allogeneic stem cell transplantation (SCT), with a dismal prognosis. Early detection of relapse enables pre-emptive treatment and may potentially reduce relapse risk, but is limited by the lack of sensitive markers for minimal residual disease (MRD). We developed a pipeline where patient-specific mutations, as determined by a myeloid next generation sequencing (NGS) panel are tracked using sensitive digital droplet PCR (ddPCR). Method We designed a prospective Nordic study (NMDSG14B; NCT02872662) enrolling all patients with MDS, mixed MDS / MPN or AML with myelodysplasia related disease and < 30% marrow blasts undergoing SCT in the Nordic region. We hypothesized that personalized MRD detection by ddPCR can predict clinical relapse earlier than conventional methods. Patients were included before SCT and serial bone marrow samples were collected before, and 1 and 3 months post SCT, and thereafter every third month for 2 years or until relapse or death. Blood samples were collected monthly. The MRD results were not available for the treating physicians. MRD positivity was defined based on the background noise of the specific ddPCR-assays and varied between 0.05-0.1% VAF. Results Three-hundred and sixteen patients were screened between 2016 and 2020, of which 19 were excluded due to lack of mutation or disease progression preventing SCT. We here present data of 254 patients followed ≥ 6 months after SCT. Median age was 64 (18-78) years and 59% were male. Most WHO subgroups of MDS (n=166), MDS/MPN (n=39), AML (n=8) and therapy-related disease (n=41), were represented. Risk profile according to IPSS-R was very low (n=13), low (n=32), intermediate (n=46), high (n=60) and very high (n=32). The majority of patients received pre-SCT treatment consisting of HMA (n=159) and / or intensive chemotherapy (n=59) while 60 patients did not receive disease-modifying treatment prior to SCT. The most common mutations were ASXL1 (n=69), TET2 (n=58), SRSF2 (n=57) and TP53 (n=44). No mutation was identified in 10 pts, and NGS data is still pending for 11 patients. After a median follow-up of 436 days, estimated 2 years overall survival and relapse free survival were 72% and 63%, respectively. Cumulative incidence of NRM and relapse at 2 years was 16% and 20%, respectively. Forty-six patients relapsed after a median of 170 (53-733) days, and the estimated median survival following relapse was 197 days. The most common pre-SCT mutations in the relapsed cohort were TP53 (n=19), DNMT3A (n=11) and RUNX1 (n=9). Thirty-seven patients died due to non-relapse mortality (NRM) after a median of 83 (4-754) days. To date, MRD results are available for 64 patients. Relapse was preceded by positive MRD in 14 out of 15 patients a median of 79 (21-173) days before clinical relapse. The 15th patient had an extra-medullary relapse only. Borderline positive MRD samples < 0.2% VAF within 100 days after SCT followed by negative samples were seen in 11 non-relapse patients. Twenty-four of 37 patients in continuous complete remission (CCR) were consistently MRD neg. Six CCR patients had positive MRD after 100 days; two with transient borderline peaks ( 0.1%, which turned negative when the patients developed GVHD; one patient with slowly decreasing MRD which turned negative first after 1 y, and finally one patient with prevailing KIT mutation (>700 days post-SCT) despite negative BCOR and STAG2. Two MRD+ patients died from NRM without showing signs of clinical relapse. Discussion In summary, we show that our pipeline of personalized MRD-assessment, based on patient-specific mutations is feasible with a high sensitivity to predict relapse. An update of study progression will be presented at the meeting. Figure 1 Disclosures Illman: Sanofi-Genzyme: Other: Travel Support; Celgene: Other: Travel Support. Mielke:DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau. Ebeling:Accord Healthcare: Other: Travel Support; Amgen: Other: Travel Support; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Otsuka Pharma Scandanavia AB: Consultancy, Membership on an entity's Board of Directors or advisory committees.

In myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), bone marrow (BM) histopathology is assessed to identify dysplastic cellular morphology, cellularity, and blast excess. Yet, other morphologic findings may elude the human eye. We used convolutional neural networks to extract morphologic features from 236 MDS, 87 MDS/MPN, and 11 control BM biopsies. These features predicted genetic and cytogenetic aberrations, prognosis, age, and gender in multivariate regression models. Highest prediction accuracy was found for TET2 [area under the receiver operating curve (AUROC) = 0.94] and spliceosome mutations (0.89) and chromosome 7 monosomy (0.89). Mutation prediction probability correlated with variant allele frequency and number of affected genes per pathway, demonstrating the algorithms' ability to identify relevant morphologic patterns. By converting regression models to texture and cellular composition, we reproduced the classical del(5q) MDS morphology consisting of hypolobulated megakaryocytes. In summary, this study highlights the potential of linking deep BM histopathology with genetics and clinical variables. Significance: Histopathology is elementary in the diagnostics of patients with MDS, but its high-dimensional data are underused. By elucidating the association of morphologic features with clinical variables and molecular genetics, this study highlights the vast potential of convolutional neural networks in understanding MDS pathology and how genetics is reflected in BM morphology. See related commentary by Elemento, p. 195.

Tiivistelmä. Tämän tutkielman tarkoitus on koota ajankohtaista tietoa yhteistoiminnallisesta oppimisesta ja siihen liittyvistä toimintatavoista, sekä siitä, miten tämä opetustapa ilmenee kouluissa. Tavoitteena on avata yhteistoiminnallisen oppimisen tausta-ajatusta vuorovaikutuksesta oppimisessa ja myös selvittää yhteistoiminnallisen oppimisen eri menetelmiä sekä työskentelytapoja. Yhteistoiminnallinen oppiminen koostuu ihmisten välisestä vuorovaikutuksesta, joten tämän käsitteen aukaiseminen on välttämätöntä, jotta yhteistoiminnallisen oppimisen idea ymmärretään oikein. Saloviita on (2006) määritellyt yhteistoiminnallisen oppimisen olevan suoraa vuorovaikusta, jossa tärkeässä roolissa on ryhmän jäsenten positiivinen riippuvuus toisistaan sekä yksilöllinen vastuu. Tämän vuorovaikutuksen aikaansaannoksena syntyy yhteinen tuotos. Yhteistoiminnallinen oppiminen on Kaganin mukaan erotettavissa muista ryhmätyöskentelymuodoista tunnuspiirteiden kautta. Näitä tunnuspiirteitä on samanaikainen vuorovaikutus, yksilöllinen vastuu, positiivinen keskinäisriippuvuus ja yhtäläinen osallistuminen (Viitattu lähteessä Kagan & Kagan, 1999). Tutkielmassa ilmeni, että yhteistoiminnallista opetusta käyttämällä opetuksesta saadaan moniulotteisempaa sekä kiinnostavampaa. Oppimisen yhteydessä oppilaat pääsevät kokemaan rakentavia keskusteluita ja kuulemaan mielenkiintoisia näkökulmia muilta oppilailta. Oppilaat pääsevät tuottamaan yhteisiä tuotoksia kantamalla yksilöllistä vastuuta mukana, joka takaa sen, että yhdessä päästään ainutlaatuisiin lopputuloksiin (Hellström, Johnson, Leppilampi & Sahlberg, 2015). Yhteistoiminnallisen oppimisen menetelmiä käyttäessä oppilaat oppivat arvokkaita taitoja, joita he tulevat tarvitsemaan tulevaisuudessa. Näitä taitoja on esimerkiksi aktiivinen osallisuus, kuunteleminen, toisten kunnioittaminen sekä itseilmaisu. Koulun arjessa yhteistoiminnallinen oppiminen ilmenee niin yksittäisinä tehtävinä kuin monen tunnin mittaisina kokonaisuuksina. Yhteistoiminnallisten menetelmien käyttöön vaikuttavat erityisesti opettajan motivaatio käyttää tätä toimintatapaa opetuksessa, sekä se, miten oppilaat käyttävät vuorovaikutustaitojaan niin, että he voisivat suoriutua yhteisistä tavoitteista.

In myelodysplastic syndrome (MDS), bone marrow (BM) histopathology is visually assessed to identify dysplastic cellular morphology, cellularity, and blast excess. Yet, many morphological findings elude the human eye. Here, we extracted visual features of 236 MDS, 87 MDS/MPN, and 10 control BM biopsies with convolutional neural networks. Unsupervised analysis distinguished underlying correlations between tissue composition, leukocyte metrics, and clinical characteristics. We applied morphological features in elastic net-regularized regression models to predict genetic and cytogenetic aberrations, prognosis, and clinical variables. By parallelizing tile, pixel, and leukocyte-level image analysis, we deconvoluted each model to texture and cellular composition to dissect their pathobiological context. Model-based mutation predictions correlated with variant allele frequency and number of affected genes per pathway, demonstrating the models’ ability to identify relevant visual patterns. In summary, this study highlights the potential of deep histopathology in hematology by unveiling the fundamental association of BM morphology with genetic and clinical determinants.

Tilaseurannassa selvitettiin valkuaislähteiden soveltuvuutta välikasvatusporsaiden liemiruokintaan, niiden vaikutuksia porsaiden tuotanto-ominaisuuksiin (päiväkasvu, rehun syönti ja rehuhyötysuhde) ja hyvinvointiin (hännänpurenta ja kuolleisuus). Tutkitut kotimaiset valkuaisrehukomponentit olivat ohravalkuaisrehu (OVR) ja härkäpapu. Seurannassa oli yhteensä 560 Duroc-kolmiroturisteytysporsasta, joiden alkupaino oli keskimäärin 9.1 kg. Porsaat jaettiin kontrolli- ja koeryhmään. Havaintoyksikkönä kokeessa oli venttiili. Jokaisella venttiilillä oli 40 porsasta. Kontrollirehu sisälsi ohraa, vehnää, kauraa, kasviöljyä, soijapohjaista täydennysrehua ja ohravalkuaisrehua. Koerehussa soijan sijaan käytettiin härkäpapua sekä härkäpapuruokinnan koostumusta täydentävää rehua. Porsailla oli kolmivaiheinen vapaa liemiruokinta ja rehunkulutusta seurattiin tilan ruokintalaitteella. Porsaat punnittiin kokeen alussa, ruokintajaksojen vaihtuessa ja kokeen lopussa. Porsaat kasvoivat keskimäärin 480 g päivässä eikä päiväkasvussa ollut tilastollisesti merkitseviä eroja ryhmien välillä. Rehunkulutus koko kokeen aikana eläintä kohti oli 342 MJ NEk ja 30.4 kg ka, eikä ryhmien välillä ollut merkitseviä eroja. Myöskään rehuhyötysuhteissa ei ryhmien välillä tullut merkitseviä eroja. Välikasvattamossa olennaista on, että porsaat kasvavat nopeasti, tasaisesti ja rehutehokkaasti välityspainoonsa. Molemmissa ruokintaryhmissä yli 75% porsaista myytiin eteenpäin 49 vuorokauden sisällä vieroituksesta. Kontrolliryhmästä suurin osa porsaista myytiin 46‒47 päivän kuluttua (54%) ja koeryhmästä 39‒40 päivän kuluttua vieroituksesta (47%). Koeryhmän porsaita jäi kuitenkin koeseurannan puitteissa merkittävästi enemmän jäljelle (21 vs 12%) suhteessa myytyjen porsaiden määrään. Tilaseurannan tulokset viittaavat siihen, että härkäpavulla ja siihen sopivilla täydennyksillä voitaisiin korvata rehun soija vilja-OVR‒pohjaisella ruokinnalla. Kontrolli- ja koeryhmän porsaiden välillä ei ollut merkittävää eroa tuotantotuloksissa. Tutkimustietoon perustuvien johtopäätösten saamiseksi vaaditaan kuitenkin jatkotutkimuksia suuremmalla havaintomäärällä tai tarkentamalla koeasetelmaa esimerkiksi porsaskohtaisin lisäpunnituksin.

ContextMutations to isocitrate dehydrogenase (IDH) appear to play a prognostic or predictive role in several neoplasias. Immunohistochemical staining designed to detect a specific R132H mutation to IDH1 showed expression in the normal adrenal cortex, raising interest to study the potential role of IDH1 in the pathogenesis of adrenocortical tumors.ObjectiveThe objective of this work is to study the role of IDH1 and its mutations in adrenocortical tumors.Design and patientsIDH1 R132H immunohistological staining was performed on a cohort of 197 adrenocortical tumors. The exon of the IDH1 gene was sequenced in 16 tumors.ResultsPositive IDH1 R132H immunohistochemical staining correlated with a better prognosis among patients with a malignant adrenocortical tumor. However, IDH1 R132H immunohistochemistry did not distinguish between local and metastasized tumors. We were unable to identify IDH1 mutations among our adrenocortical tumors using a targeted next-generation sequencing panel or via exon sequencing.ConclusionsAmong adrenocortical carcinomas, IDH1 R132H immunopositivity correlated with a better prognosis. Thus, IDH1 R132H immunohistochemical staining could serve as a prognostic or as a potential predictive marker in adrenocortical carcinomas. Further research is needed to identify the possible alterations in IDH1 that could explain our findings, because we identified no known mutations to the IDH1 gene.